Biochemical Screen for Inhibitors of Staphylococcus aureus Cell division Protein FtsZ
Lead Research Organisation:
MRC Laboratory of Molecular Biology
Abstract
Almost all bacteria rely on a molecular machine called FtsZ to divide and multiply. We are trying to find small chemical molecules which recognise FtsZ and stop it from working normally. If we can interfere with FtsZ we should be able to use these molecules as drugs to kill the bacteria which cause disease.
Technical Summary
FtsZ is the central organising molecule of bacterial cell division, and is an essential gene in almost all bacteria. FtsZ is a filament forming protein which relies on a bound GTP molecule to form a strong intra-filament interface. GTP is hydrolysed after filament formation, weakening the filament interface, this GTPase cycle ultimately drives the filament dynamics which organise bacterial cell division (Ref. 1; Fig. 1A, Supporting Data).
We propose a biochemical screen to find competitive inhibitors of GTP binding to Staphylococcus aureus FtsZ. Such inhibitors would interfere with FtsZ polymerisation and be expected to disrupt cell division. FtsZ inhibitors identified in this screen will be valuable tool compounds for FtsZ and bacterial cell division research (such compounds are currently lacking), but will also represent the starting point for the development of much-needed novel classes of anti-staphylococcal therapies. We have developed and validated an assay that is ready to enter HTS to find inhibitors in this way.
Our understanding of FtsZ biology suggests that evolution of resistance via mutation of the GTP-binding pocket will be unlikely. Compound families which inhibit S. aureus FtsZ are also likely to offer opportunities for optimisation so as to target other bacterial species, due to the extremely high degree of conservation across FtsZ GTP binding pockets (Fig. 2).
Our proposal leverages two decades of work on FtsZ structure and function in the group of Jan Löwe, and benefits from access to our established pipeline for crystallisation of S. aureus FtsZ as a tool for hit-to-lead optimisation. We anticipate that bringing the expertise of the CLD to bear in carrying out the proposed screen would result in an immensely productive collaboration very likely to produce novel FtsZ inhibitors with properties desirable for onward development into much-needed therapeutics.
We propose a biochemical screen to find competitive inhibitors of GTP binding to Staphylococcus aureus FtsZ. Such inhibitors would interfere with FtsZ polymerisation and be expected to disrupt cell division. FtsZ inhibitors identified in this screen will be valuable tool compounds for FtsZ and bacterial cell division research (such compounds are currently lacking), but will also represent the starting point for the development of much-needed novel classes of anti-staphylococcal therapies. We have developed and validated an assay that is ready to enter HTS to find inhibitors in this way.
Our understanding of FtsZ biology suggests that evolution of resistance via mutation of the GTP-binding pocket will be unlikely. Compound families which inhibit S. aureus FtsZ are also likely to offer opportunities for optimisation so as to target other bacterial species, due to the extremely high degree of conservation across FtsZ GTP binding pockets (Fig. 2).
Our proposal leverages two decades of work on FtsZ structure and function in the group of Jan Löwe, and benefits from access to our established pipeline for crystallisation of S. aureus FtsZ as a tool for hit-to-lead optimisation. We anticipate that bringing the expertise of the CLD to bear in carrying out the proposed screen would result in an immensely productive collaboration very likely to produce novel FtsZ inhibitors with properties desirable for onward development into much-needed therapeutics.
Planned Impact
Many researchers have proposed and attempted the development of novel antibacterial treatments which target FtsZ as the protein lies at the heart of the bacterial cell division process, and is essential in almost all bacteria. No anti-FtsZ molecules have yet made it to the clinic. We believe that we have identified and resolved or minimised several issues with previous approaches to finding new inhibitors of FtsZ, such that screening with our approach is likely to find both more inhibitors and, in particular, molecules which have a better chance of being developed into therapeutics. The potential impact of a novel antibiotic is immense in the face of every-increasing resistance to existing anti-bacterials, even more so for a new molecule with a novel mode of action.
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